Angewandte
Research Articles
Chemie
capability of the substituents[12] at the phenyl ring, the a-
stereoselectivity of sialylations rose gradually (70b–e, en-
tries 4–7), verifying the importance of the electronic property
of C-1 PGs for the stereoselective sialylation. As only
moderate stereoselectivity was achieved with 2-nitrobenzyl
group as the C1 PG, which has a comparable electron-
withdrawing capability as the Pic group, the electronic
property of the free Pic group cannot be invoked to explain
the a-selectivity of 2 under the standard conditions. Instead,
the protonated Pic group with a dramatically enhanced
electron-withdrawing effect should be responsible for the
high a-stereoselectivity.
sialoside exclusively at À408C under the combined effect of
catalytic amounts of AuI complex and 1.0 equivalent of TfOH
(entries 15 vs. 16). The inferior a-stereoselectivity of 2’ at
room temperature compared with that obtained at À408C
may lie in the competing sialylation of intermediates II and
II’. In the absence of TfOH, species II and II’ can serve as the
principle intermediates for products formation, hence only
moderate stereoselectivity was recorded for 2’ under the
catalysis of AuI complex (entry 2). Route c accommodates the
results of all control reactions, including the sialylation
reaction of 2b promoted by IBr/AgOTf[33] (entry 17) and the
sialylation of 69a (entry 1). In the former case the diminished
stereoselectivity could be attributed to the inefficient proto-
nation resulting from in situ generated TfOH, while the
lowered but still good stereoselectivity for donor 69a could be
credited to the presence of the protonated pyridyl group with
attenuated electron-withdrawing effect. More accurately, the
sialyl triflate IV may exist as a closely related ion pair, thus
nullifying all attempts to detect it by low temperature NMR.
To further support the mechanism route c, we investigated
several possible reactive intermediates using DFT calcula-
tions (Figure 2).[32] The results of these computational studies
(conducted on somewhat simplified structures because of
computation costs) reveal that the intermediate IV-b’ is
significantly more stable than intermediates II-b’ and II-a’ by
more than 6 kcalmolÀ1, verifying that the conversion of II/II’
to IV is thermodynamically favored. Furthermore, triflate IV-
b’ is also more stable than its a-counterpart IV-a’ by
5.0 kcalmolÀ1, strongly supporting the covalent b-triflate IV
or the closely related contact ion pair as the pivotal
intermediate in the stereoselective sialylation with 2. Inter-
estingly, opposite to the notion that the intermediate with a b-
oriented participating group at the anomeric carbon should
be thermodynamically more favored over the corresponding
a-counterpart owing to the anomeric effect in the sialyl
scaffold,[6] the II-a’ proved to be more stable than the II-b’ by
1.0 kalmolÀ1.
While it has been well documented that the PGs with high
electron-withdrawing effect on C5-NH2 can improve the
stereoselectivity of sialyl donors,[9] to the best of our knowl-
edge this is the first time that a similar but more profound PG
effect at C-1 of sialyl donor is disclosed, and this finding will
open a new avenue to access highly efficient sialylation
reactions.
Finally we aimed to show the robustness of the current
sialylation protocol by performing the reaction at room
temperature. Although the above described results have
already indicated that the here reported sialylation protocol is
less temperature sensitive than existing methods, we were
pleased to find that the sialylation between donor 2 and 3 at
room temperature led to the desired disaccharide 4 in high
yield and with excellent selectivity. Furthermore, the scal-
ability of the present sialylation protocol was also examined
showing that 4 can be generated in gram-scale from 2 and 3
with even higher stereoselectivity and yield than those
performed on small scale.
The effect of the protonated Pic on the sialylation of 2 was
subsequently evaluated. Reversing the addition sequence of
NIS/TfOH, by adding TfOH prior to NIS, halted the
sialylation of 2b, indicating a rapid protonation of 2b at low
temperature (entry 8). Surprisingly, the subsequent addition
of catalytic amounts of TfOH (0.2 eq) to the interrupted
reaction retriggered the glycosylation, eventually affording 4
with an efficiency almost equal to the standard procedure
(entry 9). Differently, for the more reactive 2a no additional
TfOH was required to promote the sialylation to reach
completion under the reversed reagent addition conditions
(entry 10). These results indicate that Pic group protonation
leads to deactivation of the donors due to the strong electron-
withdrawing effect of the protonated Pic group. The only
difference between 2a and 2b is the deactivation extent of the
protonated Pic group, which is more profound for 2b than that
for 2a. This was further substantiated by the fact that a lower
reaction temperature (À608C) largely invalidated the in-
crease in the amounts of TfOH (1.2 eq) in the sialylations with
2b, regardless whether the standard or the reversed reagent
addition procedure was adopted, leading to poor conversion
(entries 11 and 12). Further evidence was provided by the
reaction of 2b and 3 under the combined effect of MeOTf
(1.0 eq), NIS (2.4 eq), and HOTf (1.0 eq), which did not lead
to any product formation (entry 13). In contrast, methylation
of 2a with MeOTf (1.0 eq) followed by treatment with NIS
and HOTf (0.2 eq) led to stereoselective sialylation, albeit
with decreased yield (60%, entry 14). Since the methylation
of the Pic group is highly analogous to the pronation process,
the results of entries 13 and 14 clearly show that donor 2a can
be activated via route b and the protonation of the Pic group
can indeed guarantee the satisfactory a-stereoselectivity.
However, this route is not viable for 2b. Even for the reactive
2a, its activation through route b at À408C is not favored as
verified by the decreased sialylation yield.
Taking the privileged activation of the free instead of the
protonated form of donor 2 and the beneficial effect of the
protonated Pic group on the stereocontrol of sialylation into
account, route c, featuring initial formation of II and II’ and
subsequent transformation to the more stable IV under the
effect of stoichiometric amounts of TfOH, is preferred. The
formation of II and II’ could potentially facilitate the
activation of donor 2 by the participation of the Pic nitrogen
atom; while their convergent transformation to IV could
improve the a-stereoselectivity of sialylation. This mechanis-
tic proposal was supported by donor 2’, which afforded a 7/
1 mixture of a/b-sialosides at room temperature while a-
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Angew. Chem. Int. Ed. 2019, 58, 2 – 11
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